DE10116197A1 - New lipid-soluble methylprednisolone 21-ester derivatives, useful as antiinflammatory, immunosuppressive or antiallergic agents, especially in liposome formulations or lipid coatings on implants - Google Patents
New lipid-soluble methylprednisolone 21-ester derivatives, useful as antiinflammatory, immunosuppressive or antiallergic agents, especially in liposome formulations or lipid coatings on implantsInfo
- Publication number
- DE10116197A1 DE10116197A1 DE10116197A DE10116197A DE10116197A1 DE 10116197 A1 DE10116197 A1 DE 10116197A1 DE 10116197 A DE10116197 A DE 10116197A DE 10116197 A DE10116197 A DE 10116197A DE 10116197 A1 DE10116197 A1 DE 10116197A1
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- Prior art keywords
- lipid
- composition according
- liposomes
- mpl
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 39
- 239000002502 liposome Substances 0.000 title claims abstract description 31
- 239000000203 mixture Substances 0.000 title claims abstract description 27
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 title claims abstract description 16
- 238000009472 formulation Methods 0.000 title claims abstract description 12
- 238000000576 coating method Methods 0.000 title claims description 7
- 230000001506 immunosuppresive effect Effects 0.000 title claims description 5
- 239000007943 implant Substances 0.000 title claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 3
- 229960004584 methylprednisolone Drugs 0.000 title abstract description 10
- 239000002260 anti-inflammatory agent Substances 0.000 title description 2
- 239000003018 immunosuppressive agent Substances 0.000 title description 2
- 239000000043 antiallergic agent Substances 0.000 title 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 6
- 230000008685 targeting Effects 0.000 claims abstract description 5
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 3
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 3
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000001361 intraarterial administration Methods 0.000 claims description 3
- 238000007918 intramuscular administration Methods 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 239000008177 pharmaceutical agent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000232 Lipid Bilayer Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- 230000003266 anti-allergic effect Effects 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 239000003599 detergent Substances 0.000 claims description 2
- 238000000502 dialysis Methods 0.000 claims description 2
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 238000000265 homogenisation Methods 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 238000000527 sonication Methods 0.000 claims description 2
- 230000006641 stabilisation Effects 0.000 claims description 2
- 238000011105 stabilization Methods 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims 2
- 230000002685 pulmonary effect Effects 0.000 claims 2
- 238000007920 subcutaneous administration Methods 0.000 claims 2
- 230000000699 topical effect Effects 0.000 claims 2
- 239000013543 active substance Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 2
- 239000004417 polycarbonate Substances 0.000 description 11
- 238000010348 incorporation Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 239000003862 glucocorticoid Substances 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000001451 cardiotoxic effect Effects 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 238000011735 C3H mouse Methods 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Die Erfindung betrifft neue Methylprednisolonderivate mit therapeutischer Wirkung. Anwendungsgebiete sind die Medizin und die pharmazeutische Industrie.The invention relates to new methylprednisolone derivatives with a therapeutic effect. Areas of application are medicine and the pharmaceutical industry.
Methylprednisolon (MPL) ist ein Glucocorticoid, das mit dem Dexamethason und dem Hydrocortison verwandt ist. Therapeutische Anwendungsgebiete für MPL sind die Hemmung von Entzündungsreaktionen und die Immunsuppression (z. B. nach Transplantationen). Die Verbindung ist Bestandteil von mehreren Präparaten, die bereits auf dem Markt sind. Darüber hinaus gibt es Derivate von MPL, die ebenfalls Teil von pharmazeutischen Präparaten sind. Im einzelnen sind dies MPL-21-acetat, MPL-21-phosphate und MPL-21-succinat. Diese Verbindungen konnten bisher noch nicht liposomal verkapselt werden. In US-PS 4,693,999 ist unter anderem die Palmitoylierung einer Reihe von Glucocorticoiden beschrieben, die dem Einbau in Liposomen dienen. Als Glucocorticoid ist Methylprednisolon nicht aufgeführt. Im US-PS 5,190,936 ist der Einbau von marktüblichen Derivaten von Glucocorticoiden in Liposomen beschrieben. Hier ist das Derivat MPL-21-acetat aufgeführt. Die Möglichkeit der Inkorporation in Beschichtungen ist in beiden Patenten nicht beschrieben.Methylprednisolone (MPL) is a glucocorticoid that works with the dexamethasone and the Hydrocortisone is related. Therapeutic areas of application for MPL are inhibition of inflammatory reactions and immunosuppression (e.g. after transplants). The Connection is part of several preparations that are already on the market. About that there are also derivatives of MPL, which are also part of pharmaceutical preparations. Specifically, these are MPL-21 acetate, MPL-21 phosphate and MPL-21 succinate. This Compounds have not yet been encapsulated liposomally. In U.S. Patent 4,693,999 describes, inter alia, the palmitoylation of a number of glucocorticoids which the Incorporation into liposomes. Methylprednisolone is not listed as a glucocorticoid. in the US Pat. No. 5,190,936 is the incorporation of commercially available derivatives of glucocorticoids in Liposomes described. The derivative MPL-21 acetate is listed here. The possibility of Incorporation in coatings is not described in either patent.
Die bisherigen MPL-Formulierungen haben den Nachteil, dass sie schnell aus der Zirkulation entfernt werden (Clearance), in hohen Dosen schädliche Nebenwirkungen haben und potentiell cardiotoxisch sind. Die Cardiotoxizität beruht darauf, dass die relativ kleinen Moleküle (im Gegensatz zu Liposomen) in den Herzmuskel eindiffundieren können.The previous MPL formulations have the disadvantage that they quickly get out of circulation are removed (clearance), have harmful side effects in high doses and are potentially cardiotoxic. The cardiotoxicity is due to the relatively small Molecules (unlike liposomes) can diffuse into the heart muscle.
Der Erfindung lag die Aufgabe zugrunde, lipidlösliche MPL-Derivate für alternative Darreichungsformen zu finden.The invention was based on the object of lipid-soluble MPL derivatives for alternative Find dosage forms.
Die Erfindung wird gemäß den Patentansprüchen realisiert. Gemäß der Erfindung wurden
lipidlösliche Methylprednisolon-Derivate der allgemeinen Formel I entwickelt,
The invention is implemented in accordance with the patent claims. According to the invention, lipid-soluble methylprednisolone derivatives of the general formula I were developed
wobei R eine Monocarbonsäure mit einer unverzweigten Alkylkette der Länge C9 bis C19 ist. Bevorzugt ist eine Verbindung mit R=Palmitoyl. where R is a monocarboxylic acid with an unbranched alkyl chain of length C9 to C19. A compound with R = palmitoyl is preferred.
Diese Verbindungen lassen sich (im Gegensatz zu MPL und seinen bekannten Derivaten) in Lipidschichten integrieren. Sinn der Lipidintegration der Verbindungen I sind neue Darreichungsformen für den Wirkstoff.These compounds can (in contrast to MPL and its known derivatives) in Integrate lipid layers. The lipid integration of compounds I is new Dosage forms for the active ingredient.
Zum Umfang der Erfindung gehören auch pharmazeutische Mittel, die aus einer liposomalen
Formulierung der Verbindungen I zusammen mit einer oder mehreren Komponenten aus einer
oder mehreren der folgenden Gruppen bestehen:
The scope of the invention also includes pharmaceutical compositions which consist of a liposomal formulation of the compounds I together with one or more components from one or more of the following groups:
- a) natürliche, halbsynthetische oder vollsynthetische Amphiphilea) natural, semi-synthetic or fully synthetic amphiphiles
- b) Cholesterinb) cholesterol
- c) Tetraetherlipid-Derivatec) tetraether derivatives
- d) Lipide mit hydrophilen Polymeren als Kopfgrupped) lipids with hydrophilic polymers as head group
- e) Lipide, die einen Liganden für die Zielsteuerung des Liposoms enthalten.e) Lipids containing a ligand for targeting the liposome.
Ein bevorzugtes Mittel enthält ein Mol-Verhältnis von I zu den Lipiden der Gruppen a)-e) von 1 : 100 bis 1 : 1.A preferred agent contains a molar ratio of I to the lipids of groups a) -e) of 1: 100 to 1: 1.
Das Amphiphil der Gruppe a) ist bevorzugt ein Phospholipid wie z. B. Phosphatidylcholin,
Phosphatidylethanolamin, Phosphatidylglycerol, Phosphatidsäure oder Sphingomyelin.
Das Tetraetherlipid aus der Gruppe c) entspricht einer der folgenden Formeln:
The amphiphile of group a) is preferably a phospholipid such as. As phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid or sphingomyelin. The tetraether lipid from group c) corresponds to one of the following formulas:
mit S1 und S2 Kopfgruppen, die in der Deutschen Patentanmeldung 100 65 561.0 beschrieben sind.with S 1 and S 2 head groups, which are described in German patent application 100 65 561.0.
Das Lipid der Gruppe d) ist bevorzugt ein Polyethylenglycol-Lipid (PEG-Lipid).The group d) lipid is preferably a polyethylene glycol lipid (PEG lipid).
In einer besonderen Ausführungsform der Erfindung kann das Lipid der Gruppe e) mit einem Peptid gekoppelt sein. In a particular embodiment of the invention, the lipid of group e) can be treated with a Be coupled peptide.
Die Liposomen für die erfindungsgemäßen Mittel werden üblicherweise durch Homogenisierung, Extrusion, Detergenz-Dialyse, Beschallung, Dehydratisierung/ Rehydratisierung, oder Ethanol-Injektion hergestellt.The liposomes for the agents according to the invention are usually by Homogenization, extrusion, detergent dialysis, sonication, dehydration / Rehydration, or ethanol injection.
Sie weisen bevorzugt eine oder mehrere Lipiddoppelschichten auf und haben eine Partikel- Grösse zwischen 10 nm und 5 µm, bevorzugt zwischen 50 nm und 1 µm.They preferably have one or more lipid bilayers and have a particle Size between 10 nm and 5 µm, preferably between 50 nm and 1 µm.
Eine Dehydratisierung der Liposomen erfolgt durch Lyophilisation oder eine andere Trocknungsmethode.Liposomes are dehydrated by lyophilization or another Drying method.
Das Verabreichen des Mittels erfolgt üblicherweise nach Zusatz von geeigneten Hilfsstoffen auf folgenden Wegen: oral, enteral, parenteral, intravenös, intraarteriell, intramuskulär, topisch, subcutan, pulmonal oder intraperitoneal.The agent is usually administered after the addition of suitable auxiliaries in the following ways: oral, enteral, parenteral, intravenous, intraarterial, intramuscular, topically, subcutaneously, pulmonally or intraperitoneally.
Das pharmazeutische Mittel, kann auch aus einer Formulierung der Verbindungen I in einer Dispersion aus einer mit Wasser nicht mischbaren Flüssigkeit in einer kontinuierlichen Wasserphase bestehen. Die mit Wasser nicht mischbare Flüssigkeit ist bevorzugt ein natürliches oder synthetisches Öl. Zur Stabilisierung können ferner oberflächenaktive Substanzen zugesetzt werden.The pharmaceutical agent can also be obtained from a formulation of the compounds I in a Dispersion from a water-immiscible liquid in a continuous Water phase exist. The water-immiscible liquid is preferably a natural or synthetic oil. Surface stabilizers can also be used for stabilization Substances are added.
Auch dieses letztgenannte Mittel kann nach Zusatz von geeigneten Hilfsstoffen auf folgenden Wegen verabreicht werden: oral, enteral, parenteral, intravenös, intraarteriell, intramuskulär, topisch, subcutan, pulmonal oder intraperitoneal.This last-mentioned agent can also have the following after the addition of suitable auxiliary substances Because of being administered: orally, enterally, parenterally, intravenously, intraarterially, intramuscularly, topically, subcutaneously, pulmonally or intraperitoneally.
Das pharmazeutische Mittel, bestehend aus einer Lipidschicht, in die die Verbindung I eingelagert ist, läßt sich vorteilhaft auch als Beschichtung auf medizinischen Geräten oder Implantaten einsetzen.The pharmaceutical composition consisting of a lipid layer in which the compound I is stored, can also advantageously as a coating on medical devices or Insert implants.
Die Verwendung der erfindungsgemäßen pharmazeutischen Mittel erfolgt bevorzugt als antiinflammatorisches, als immunsupressives und/oder als antiallergisches Therapeutikum.The pharmaceutical compositions according to the invention are preferably used as anti-inflammatory, as an immunosuppressive and / or as an anti-allergic therapeutic.
Die liposomalen Formulierungen der Verbindungen I sind dadurch gekennzeichnet, daß sie in die Matrix des Liposoms eingebaut werden. Durch den Einbau in Liposomen läßt sich die Halbwertszeit der Verbindung im Körper deutlich erhöhen. Darüber hinaus bietet die liposomale Formulierung der Verbindungen I eine Möglichkeit, die Freisetzung der Verbindungen zeitlich zu kontrollieren ("controlled release"), was lokale Überdosierungen vermeidet. So kann die cardiotoxische Wirkung der Verbindungen gemäß der Erfindung durch eine liposomale Formulierung vermieden werden. Des weiteren bieten Liposomen eine Möglichkeit der Zielsteuerung von Wirkstoffen ("Targeting"). The liposomal formulations of the compounds I are characterized in that they are in the matrix of the liposome can be incorporated. By incorporation into liposomes, the Significantly increase the half-life of the compound in the body. In addition, the Liposomal formulation of the compounds I a way to release the Controlling connections in time ("controlled release"), which indicates local overdoses avoids. So the cardiotoxic effect of the compounds according to the invention can be avoided by a liposomal formulation. Furthermore, liposomes offer one Possibility of targeting active ingredients ("targeting").
Insgesamt liegen die Vorteile einer liposomalen Formulierung der Verbindungen I in der Steigerung der Effektivität des Medikaments, der längeren Wirksamkeit und der geringeren Nebenwirkung.Overall, the advantages of a liposomal formulation of the compounds I are in the Increasing the effectiveness of the drug, the longer effectiveness and the lower Side effect.
Eine weitere Anwendungsmöglichkeit der neuen Derivate besteht in der Inkorporation in Beschichtungen.Another application of the new derivatives is incorporation in Coatings.
Implantate (Stents, Prothesen) bergen das Risiko von Entzündungs- und Abstoßungsreaktionen, zur Steigerung der Biokompatibilität können die Oberflächen mit Lipiden beschichtet werden. Gemäß der Erfindung wird das MPL-Palmitat in Beschichtungen, bestehend aus Lipiden, auf die Oberfläche von Implantaten integriert und kann vor Ort als entzündungshemmende Substanz wirken. Für Lipidschichten ist prinzipiell die gleiche Release-Charakteristik gegeben wie für Liposomen. Besonders vorteilhaft ist es, Tetraetherlipid-Derivate zu benutzen, da sie besonders stabile Schichten ausbilden und sich deshalb hervorragend für Beschichtungen eignen. Implants (stents, prostheses) carry the risk of inflammation and Rejection reactions, to increase the biocompatibility, the surfaces with Lipids are coated. According to the invention, the MPL palmitate in Coatings consisting of lipids, integrated on the surface of implants and can act as an anti-inflammatory substance on site. In principle for lipid layers the same release characteristics as for liposomes. It is particularly advantageous To use tetraether lipid derivatives because they form particularly stable layers and themselves therefore ideal for coatings.
Die Erfindung soll nachfolgend durch Anwendungsbeispiele näher erläutert werden.The invention will be explained in more detail below by application examples.
250 mg (668 µmol) MPL werden unter Stickstoff in 10 ml trockenem Pyridin gelöst und auf
0-4°C abgekühlt. Nach Zugabe von 182 µl (601 µmol) Palmitoylchlorid wird die Lösung 18 h
bei 4°C gerührt. Das Lösungsmittel wird verdampft und der Rückstand mit 50 ml
Ethanol/Wasser (4 : 1) aufgenommen und wieder einrotiert. Das Rohprodukt wird durch
Chromatographie mit CHCl3/EtOAc (1 : 1) gereinigt. Man erhält 262 mg MPL-P (71%).
Analytik:
250 mg (668 µmol) MPL are dissolved in 10 ml dry pyridine under nitrogen and cooled to 0-4 ° C. After adding 182 μl (601 μmol) palmitoyl chloride, the solution is stirred at 4 ° C. for 18 h. The solvent is evaporated and the residue is taken up in 50 ml of ethanol / water (4: 1) and concentrated again. The crude product is purified by chromatography with CHCl 3 / EtOAc (1: 1). 262 mg of MPL-P (71%) are obtained. analytics:
- - MS (DEI+); m/z (%) [Fragment]: 613 (45) [M+], 357 (13) [M+-C16H32O2 (Palmitinsäure)], 256 (51) [C16H32O2 + (Palmitinsäure)], 136 (100), 135 (100).- MS (DEI + ); m / z (%) [fragment]: 613 (45) [M + ], 357 (13) [M + -C 16 H 32 O 2 (palmitic acid)], 256 (51) [C 16 H 32 O 2 + (Palmitic acid)], 136 (100), 135 (100).
- - IR (Film): = 3400 cm-1 (breit, OH, H2O), 2923, 2853 (aliph. C-H), 1722 (C=O, Ester und gesättigte Ketogruppe), 1657 (C=O, α,β,α'β'-ungesättigt), 1613 (C=C, α,β,α'β'-ungesättigt)- IR (film): = 3400 cm -1 (broad, OH, H 2 O), 2923, 2853 (aliph. CH), 1722 (C = O, ester and saturated keto group), 1657 (C = O, α, β, α'β'-unsaturated), 1613 (C = C, α, β, α'β'-unsaturated)
MPLP wird mit Phosphatidylcholin (PC; aus Eiweiß) in wechselnden Verhältnissen gemischt und in 1 ml Chloroform : Methanol 1 : 1 (v/v) aufgenommen (CHCl3 : MeOH). Die Gesamtlipidmenge (PC + MPLP) beträgt 8 mg, der MPLP-Anteil beträgt maximal 0,8 mg (10 Massen-Prozent). Nach Hinzufügen von einigen Glasperlen wird die Mischung in einem Glaskolben am Rotationsverdampfer eingedampft, so dass ein transparenter Lipidfilm entsteht. Nach Zugabe von 1 ml Puffer (10 mM HEPES, 150 mM NaCl, pH 7,4) wird der Lipidfilm unter Rotation des Glaskolbens über Nacht hydratisiert. Die Lipiddispersion wird kurz im Ultraschallbad beschallt und anschließend durch eine Polycarbonat-Membran extrudiert (Porengröße 200 nm). Dabei entstehen Liposomen mit einer mittleren Größe von ca. 200 nm (Messung durch quasi-elastische Lichtstreuung).MPLP is mixed with phosphatidylcholine (PC; from protein) in changing ratios and taken up in 1 ml chloroform: methanol 1: 1 (v / v) (CHCl 3 : MeOH). The total amount of lipid (PC + MPLP) is 8 mg, the maximum MPLP content is 0.8 mg (10% by mass). After adding a few glass beads, the mixture is evaporated in a glass flask on a rotary evaporator, so that a transparent lipid film is formed. After adding 1 ml of buffer (10 mM HEPES, 150 mM NaCl, pH 7.4), the lipid film is hydrated overnight while rotating the glass flask. The lipid dispersion is briefly sonicated in an ultrasonic bath and then extruded through a polycarbonate membrane (pore size 200 nm). This results in liposomes with an average size of approx. 200 nm (measurement by quasi-elastic light scattering).
Um die Liposomen von nicht eingebautem MPL-P zu trennen werden sie einer Größenausschlußchromatographie an Sephadex G75 unterzogen und in 1 ml-Fraktionen aufgefangen (Laufpuffer: Liposomenpuffer, s. o.; Gelbett 1 cm ∅, 25 cm Länge). Der Gehalt an PC in den Fraktionen wird durch einen enzymatischen Cholin-Test bestimmt (PAP 150, Biomerieux GmbH, Nürtingen). Als Liposomen-enthaltende Fraktionen werden die Fraktionen angenommen, die den größten PC-Anteil aufweisen. Zur Bestimmung des MPL-P- Gehaltes werden von den Liposomen-enthaltenden Fraktionen jeweils 100 µl entnommen und mit dem 4-fachen-Volumen an CHCl3 : MeOH 2 : 1 (w/v) extrahiert. Die Extrakte werden eingeengt und zusammen mit einer Eichreihe von MPL-P auf eine HPTLC-Platte (Merck, Darmstadt) aufgetragen. Die Entwicklung erfolgt im Laufmittel CHCl3 : Ethylactat 1 : 1. Anschließend wird die Platte in eine Färbelösung gedippt (3% (w/v) Kupferacetat; 8% (v/v) Phosphorsäure) und 15 min bei 180°C erhitzt. Die HPTLC-Platte wird mit einem Computer- Scanner (Epson Perfection 610, Düsseldorf) eingescannt und die Banden werden einer Graustufenanalyse unterzogen. Der MPL-P-Gehalt der Proben ergibt sich aus dem Vergleich des Graustufenwertes seiner Bande mit den Banden der Eichreihe.In order to separate the liposomes from non-incorporated MPL-P, they are subjected to size exclusion chromatography on Sephadex G75 and collected in 1 ml fractions (running buffer: liposome buffer, see above; gel bed 1 cm cm, 25 cm long). The PC content in the fractions is determined by an enzymatic choline test (PAP 150, Biomerieux GmbH, Nürtingen). The fractions which have the largest PC content are assumed to be fractions containing liposomes. To determine the MPL-P content, 100 μl are taken from the fractions containing liposomes and extracted with 4 times the volume of CHCl 3 : MeOH 2: 1 (w / v). The extracts are concentrated and applied together with a calibration series from MPL-P to an HPTLC plate (Merck, Darmstadt). Development takes place in the mobile phase CHCl 3 : ethyl acetate 1: 1. Then the plate is dipped in a coloring solution (3% (w / v) copper acetate; 8% (v / v) phosphoric acid) and heated at 180 ° C for 15 min. The HPTLC plate is scanned with a computer scanner (Epson Perfection 610, Düsseldorf) and the bands are subjected to a grayscale analysis. The MPL-P content of the samples is obtained by comparing the gray scale value of its band with the bands of the calibration series.
Aus der Zusammensetzung der Liposomen läßt sich der Gewichtsanteil des MPL-P im Liposom berechnen. Die Inkorporationseffizienz ergibt sich als Quotient des gefundenen durch den theoretischen MPL-P-Gehalt des Liposoms. In Abb. 1 ist der gefundene MPL-P- Gehalt in Abhängigkeit vom theoretischen MPL-P-Gehalt in verschiedenen nach 2.1. hergestellten Liposomen dargestellt. MPL-P läßt sich bei einem Massenverhältnis MPL-P : PC von 2 : 98 mit einer Inkorporationseffizienz von 100% in PC-Liposomen einbauen. Bei einem Massenverhältnis MPL-P : PC von 10 : 90 sinkt die Inkorporationseffizienz auf 55%. Es sind Liposomen aus PC darstellbar, die mindestens 5, 5 Massen-% MPL-P enthalten.The weight fraction of the MPL-P in the liposome can be calculated from the composition of the liposomes. The incorporation efficiency results as the quotient of the found by the theoretical MPL-P content of the liposome. Fig. 1 shows the MPL-P content found depending on the theoretical MPL-P content in different according to 2.1. prepared liposomes shown. MPL-P can be built into PC liposomes at a mass ratio of MPL-P: PC of 2: 98 with an incorporation efficiency of 100%. With an MPL-P: PC mass ratio of 10:90, the incorporation efficiency drops to 55%. Liposomes made of PC can be represented which contain at least 5.5% by mass of MPL-P.
Durch Zusatz von Tetraetherlipid-Derivaten (5 Massen%)läßt sich die Inkorporationseffizienz bei einem MPL-P : PC-Verhältnis von 8 : 92 von 60% auf 85% steigern (siehe Abb. 1).By adding tetraether lipid derivatives (5% by mass), the incorporation efficiency can be increased from 60% to 85% at an MPL-P: PC ratio of 8:92 (see Fig. 1).
Die Wirkung von MPL-P als immunsupressive Substanz wurde in einem Tierversuch überprüft. T-Lymphocyten lassen sich durch Glucocortcoide wie z. B. Dexamethason in die Apoptose führen. Männlichen C3H-Mäusen (4 Monate alt, ca. 20 g Gewicht) wurden 200 µg MPLP intraperitoneal appliziert. Das MPL-P lag in einer liposomalen Formulierung aus PC mit einem Gehalt von 3 mol% MPL-P vor und das Injektionsvolumen betrug 200 µl. Nach 48 h wurden die Mäuse getötet, die Thymus-Drüse entfernt und die Thymocyten isoliert. T-Lymphocyten wurden durch CD4- und CD8-spezifische Antikörper markiert und in einer FACS-Analyse gezählt (vgl. Sentman et al., Cell, 67, 879-888). Der Anteil der lebenden CD4/CD-8-positiven Zellen an den insgesamt gezählten Zellen ergibt die Überlebensrate der T-Lymphocyten. In Abb. 2 ist die Überlebensrate der T-Lymphocyten einer mit MPL-P- behandelten Maus dem Normalwert einer unbehandelten Maus gegenübergestellt. Das deutliche Herabsenken der T-Lymphocyten-Rate in der MPL-Pbehandelten Maus spiegelt deutlich den immunsupressiven Effekt von MPL-P wider (siehe Abb. 2).The effect of MPL-P as an immunosuppressive substance was checked in an animal experiment. T lymphocytes can be glucocortcoids such as. B. lead dexamethasone into apoptosis. Male C3H mice (4 months old, approx. 20 g in weight) were administered 200 µg MPLP intraperitoneally. The MPL-P was in a liposomal formulation made of PC with a content of 3 mol% MPL-P and the injection volume was 200 µl. After 48 hours the mice were sacrificed, the thymus removed and the thymocytes isolated. T lymphocytes were labeled by CD4 and CD8 specific antibodies and counted in a FACS analysis (see Sentman et al., Cell, 67, 879-888). The proportion of living CD4 / CD-8 positive cells in the total number of cells counted gives the survival rate of the T lymphocytes. In Fig. 2, the survival rate of the T lymphocytes of a mouse treated with MPL-P is compared to the normal value of an untreated mouse. The significant lowering of the T-lymphocyte rate in the MPL-P-treated mouse clearly reflects the immunosuppressive effect of MPL-P (see Fig. 2).
Claims (23)
wobei R eine Monocarbonsäure mit einer unverzweigten Alkylkette der Länge C9 bis C19 ist.1. Methylprednisolone derivative of the formula I.
where R is a monocarboxylic acid with an unbranched alkyl chain of length C9 to C19.
2. Methylprednisolone-21-palmitate of the formula Ia
- a) natürliche, halbsynthetische oder vollsynthetische Amphiphile
- b) Cholesterin
- c) Tetraetherlipid-Derivate
- d) Lipide mit hydrophilen Polymeren als Kopfgruppe
- e) Lipide, die einen Liganden für die Zielsteuerung des Liposoms enthalten.
- a) natural, semi-synthetic or fully synthetic amphiphiles
- b) cholesterol
- c) tetraether lipid derivatives
- d) lipids with hydrophilic polymers as head group
- e) Lipids containing a ligand for targeting the liposome.
mit S1 und S2 Kopfgruppen, die in der Deutschen Patentanmeldung 100 65 561.0 beschrieben sind.6. Composition according to claim 3, characterized in that the tetraether lipid from group c) corresponds to one of the following general formulas:
with S 1 and S 2 head groups, which are described in German patent application 100 65 561.0.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10116197A DE10116197A1 (en) | 2001-03-30 | 2001-03-30 | New lipid-soluble methylprednisolone 21-ester derivatives, useful as antiinflammatory, immunosuppressive or antiallergic agents, especially in liposome formulations or lipid coatings on implants |
| PCT/EP2002/003631 WO2002094282A2 (en) | 2001-03-30 | 2002-04-02 | Compositions with methylprednisolone derivatives having therapeutic effect |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10116197A DE10116197A1 (en) | 2001-03-30 | 2001-03-30 | New lipid-soluble methylprednisolone 21-ester derivatives, useful as antiinflammatory, immunosuppressive or antiallergic agents, especially in liposome formulations or lipid coatings on implants |
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| WO (1) | WO2002094282A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10249401A1 (en) * | 2002-10-23 | 2004-05-13 | Bernina Biosystems Gmbh | Liposome forming composition |
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| WO2017040702A1 (en) * | 2015-08-31 | 2017-03-09 | The Regents Of The University Of California | Bipolar tetraether lipids |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0381286A (en) * | 1989-08-22 | 1991-04-05 | Green Cross Corp:The | Steroid external medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8403905D0 (en) * | 1984-07-30 | 1984-07-30 | Draco Ab | LIPOSOMES AND STEROID ESTERS |
| US5356633A (en) * | 1989-10-20 | 1994-10-18 | Liposome Technology, Inc. | Method of treatment of inflamed tissues |
| AU1579092A (en) * | 1991-02-27 | 1992-10-06 | Nova Pharmaceutical Corporation | Anti-infective and anti-inflammatory releasing systems for medical devices |
| DE19607722A1 (en) * | 1996-02-29 | 1997-09-04 | Freisleben H J Dr | Tetraether lipids and liposomes containing them and their use |
-
2001
- 2001-03-30 DE DE10116197A patent/DE10116197A1/en not_active Withdrawn
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- 2002-04-02 WO PCT/EP2002/003631 patent/WO2002094282A2/en not_active Ceased
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0381286A (en) * | 1989-08-22 | 1991-04-05 | Green Cross Corp:The | Steroid external medicine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10249401A1 (en) * | 2002-10-23 | 2004-05-13 | Bernina Biosystems Gmbh | Liposome forming composition |
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| WO2002094282A3 (en) | 2003-09-25 |
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